Core Safety Profile. Pharmaceutical form(s)/strength: Concentrate and solvent for solution for infusion, 10mg/ml. Date of FAR:

Transcription

1 Core Safety Profile Active substance: Itroconazole Pharmaceutical form(s)/strength: Concentrate and solvent for solution for infusion, 10mg/ml P - RMS: UK/H/PSUR/0033/001 Date of FAR:

2 CORE SAFETY PROFILE Based on the EU SmPC sections

3 NAME OF THE MEDICINAL PRODUCT /.../ 10 mg/ml concentrate and solvent for solution for infusion. 4.3 Contraindications /.../ is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients. /.../ cannot be used when administration of Sodium Chloride Injection is contraindicated. The excipient hydroxypropyl- -cyclodextrin is eliminated through glomerular filtration. Therefore, /.../ is contraindicated in patients with severe renal impairment defined as creatinine clearance below 30 ml/min (see section 4.4 and 5.2). Coadministration of the following drugs is contraindicated with /.../ (see section 4.5): CYP3A4 metabolised substrates that can prolong the QT-interval e.g., terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, levacetylmethadol (levomethadyl), quinidine, sertindole, or pimozide coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes. CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, simvastatin and lovastatin Triazolam and oral midazolam. Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine). Eletriptan. Nisoldipine /.../ must not be used during pregnancy for non life-threatening indications (see section 4.6). 4.4 Special warnings and precautions for use Cross hypersensitivity There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing /.../ to patients with hypersensitivity to other azoles Cardiac effects In a healthy volunteer study with /.../, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. A similar investigation was not performed in the target patient population. Itraconazole has been shown to have a negative inotropic effect and /.../ has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole. /.../ should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. Physicians should carefully review the risks and benefits of /.../ therapy for patients with known risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischaemic and

4 valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, /.../ should be discontinued. Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5). Hepatic effects Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of /.../. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving /.../ treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking itraconazole. Interaction potential /.../ has a potential for clinically important drug interactions (see section 4.5). Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John s wort)). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure. Use in children Since clinical data on the use of /.../ in paediatric patients are unavailable, /.../ should not be used in children unless the potential benefit outweighs the potential risk. Use in elderly Since clinical data of the use of /.../ in elderly patients are limited, it is advised to use /.../ in these patients only if the potential benefit outweighs the potential risk. Hepatic effects Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of /.../. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving /.../ treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking itraconazole. Hepatic impairment

5 Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered to this patient population (see sections 4.2 and 5.2). Renal impairment Hydroxypropyl- -cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with renal impairment defined as creatinine clearance below 30 ml/min /.../ is contraindicated (see sections 4.3 and 5.2). /.../ should be used with caution in patients with a lesser degree of renal failure. In patients with mild and moderate renal impairment, serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation (see section 4.4). Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see sections 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Neuropathy If neuropathy occurs that may be attributable to /.../, the treatment should be discontinued. Cross hypersensitivity There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing /.../ to patients with hypersensitivity to other azoles. Cross-resistance In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of itraconazole therapy. Cardiac effects In a healthy volunteer study with /.../, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. A similar investigation was not performed in the target patient population. Itraconazole has been shown to have a negative inotropic effect and /.../ has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole. /.../ should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. Physicians should carefully review the risks and benefits of /.../ therapy for patients with known risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischaemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, /.../ should be discontinued. Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5).

6 Interaction potential /.../ has a potential for clinically important drug interactions (see section 4.5). Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John s wort)). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure. Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see sections 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. 4.5 Interaction with other medicinal products and other forms of interaction Drugs affecting the metabolism of itraconazole Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John s Wort), phenobarbital and isoniazid but similar effects should be anticipated. Potent inhibitors of CYP3A4 such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole. Effect of itraconazole on the metabolism of other drugs Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered. Drugs which are contraindicated with itraconazole: Terfenadine, astemizole, bepridil, mizolastine, levacetylmethadol (levomethadyl), cisapride, dofetilide, quinidine, sertindole or pimozide are contraindicated with SPORANOX IV since coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3). CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, simvastatin and lovastatin Triazolam and oral midazolam. Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine). Eletriptan Nisoldipine Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

7 The following drugs should be used with caution and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with itraconazole, should be reduced if necessary: Oral anticoagulants; HIV protease inhibitors such as ritonavir, indinavir, saquinavir; Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate; CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil; Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as cerivastatin (see also drugs which are contraindicated with itraconazole). Certain immunosuppressive agents: cyclosporine, tacrolimus, rapamycin (also known as sirolimus); Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone; Digoxin (via inhibition of P-glycoprotein) Others: carbamazepine, cilostazol, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, disopyramide, ebastine, fentanyl, halofantrine, repaglinide and reboxetine. The importance of the concentration increase and clinical relevance of these changes during coadministration with itraconazole remain to be established. No interaction of itraconazole with zidovudine (AZT) and fluvastatine has been observed. No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed. Effect on protein binding In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine. 4.6 Pregnancy and lactation Pregnancy /.../ must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see section 4.3). In animal studies itraconazole shows reproduction toxicity (see section 5.3). Epidemiological data on exposure to /.../ during the first trimester of pregnancy mostly in patients receiving short-term treatment for vulvovaginal candidosis did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens. Women of childbearing potential Women of childbearing potential receiving /.../ should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of /.../ therapy. Lactation A very small amount of itraconazole is excreted in human milk and must not be administered to lactating women. Breast-feeding is to be discontinued prior to taking itraconazole. 4.7 Effects on ability to drive and use machines No effects have been observed. No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as

8 dizziness, visual disturbances and hearing loss (see section 4.8), which may occur in some instances, must be taken into account. 4.8 Undesirable effects In clinical trials with intravenous itraconazole, the most frequently reported adverse experiences were of gastrointestinal, metabolic and nutritional, and hepatobiliary origin. The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention: Very common ( 1/10); Common ( 1/100 to < 1/10); Uncommon ( 1/1,000 to < 1/100); Rare ( 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data). Adverse Drug Reactions Blood and lymphatic system disorders Not Known Leukopenia, neutropenia, thrombocytopenia Immune system disorders Not Known Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity* Metabolism and nutrition disorders Common Hypokalemia Uncommon Hyperglycaemia Not Known Hypertriglyceridemia Nervous system disorders Common Headache, Dizziness Uncommon Hypoaesthesia Not Known Peripheral Neuropathy*, Paraesthesia Eye disorders Uncommon Visual Disorders, including Vision Blurred and Diplopia Ear and labyrinth disorder Uncommon Transient or permanent hearing loss* Not Known Tinnitus Cardiac disorders Not Known Congestive Heart Failure*, Hypertension Respiratory, thoracic and mediastinal disorders Uncommon Pulmonary Oedema Gastrointestinal disorders Very Common Nausea Common Abdominal Pain, Vomiting, Diarrhea, Constipation Uncommon Dysgeusia Not Known Pancreatitis, Dyspepsia Hepato-biliary disorders

9 Common Not Known Hepatitis, Jaundice, Hyperbilirubinaemia, Hepatic Enzymes Increased Hepatotoxicity*, Acute Hepatic Failure* Skin and subcutaneous tissue disorders Common Rash, Pruritus Not Known Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis,, Urticaria, Alopecia, Photosensitivity Musculoskeletal and connective tissue disorders Uncommon Myalgia Not Known Arthralgia Renal and urinary disorders Not Known Pollakiuria, urinary incontinence Reproductive system and breast disorders Not Known Menstrual Disorders, Erectile Dysfunction General disorders and administration site conditions Common Oedema, Pyrexia * Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see section 4.4). 4.9 Overdose In the event of overdose, supportive measures should be employed. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.